Human multiple myeloma is a malignancy of hematopoietic stem cell origin which manifests itself at the mature stage of B-cell development. The present studies examine biological approaches to the treatment of human myeloma. Interleukin-6 (IL-6) has been shown to be an autocrine or paracrine growth factor for myeloma cells. One human myeloma cell line, U-266, is growth inhibited by monoclonal antibodies (MAb) to IL-6 and will be used in IL-6 signaling studies and in vivo models of human myeloma in nude or scid mice. In conjunction with these studies, MAb to IL-6 and the IL-6 receptor will be used in a clinical trial of myeloma patients at the BRMP. As human myeloma cell lines have been traditionally difficult to establish, we have recently established a human myeloma line from an IgG myeloma patient. This cell line and additional myeloma cell lines will also be utilized for in vitro and in vivo studies on the effects of cytokines and chemotherapeutic drugs on myeloma growth and differentiation. We have observed that several agents, including IFNAlpha, retinoid acid, phorbol esters, ionomycin, and hexamethylene bisacetamide, which in other systems promote cellular differentiation, inhibit myeloma cell line growth. We are currently investigating the mechanism by which these agents act on myeloma cells and extending these findings to in vivo myeloma model systems.